Targeting transcriptional regulation of SARS-CoV-2 entry factors <i>ACE2</i> and <i>TMPRSS2</i>.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for COVID-19, employs two key host proteins to gain entry and replicate within cells, angiotensin-converting enzyme 2 (ACE2) and the cell surface transmembrane protease serine 2 (TMPRSS2). <i>TMPRSS2</i> was first characterized as an androgen-regulated gene in the prostate. Supporting a role for sex hormones, males relative to females are disproportionately affected by COVID-19 in terms of mortality and morbidity. Several studies, including one employing a large epidemiological cohort, suggested that blocking androgen signaling is protective against COVID-19. Here, we demonstrate that androgens regulate the expression of <i>ACE2</i>, <i>TMPRSS2</i>, and androgen receptor (AR) in subsets of lung epithelial cells. AR levels are markedly elevated in males relative to females greater than 70 y of age. In males greater than 70 y old, smoking was associated with elevated levels of AR and ACE2 in lung epithelial cells. Transcriptional repression of the AR enhanceosome with AR or bromodomain and extraterminal domain (BET) antagonists inhibited SARS-CoV-2 infection in vitro. Taken together, these studies support further investigation of transcriptional inhibition of critical host factors in the treatment or prevention of COVID-19.

Apel IJ, Bawa P, Cao X, Cheng Y, Chinnaiyan AM, Delekta AD, Ellison SJ, Kregel S, Mannan R, McMurry L, Mehra R, Mei Z, Narayanan SP, Parolia A, Pitchiaya S, Pretto CD, Qiao Y, Raskind G, Robinson DR, Sexton JZ, Simko SA, Su F, Tien JC, Wang R, Wang S, Wang XM, Wotring JW, Wu YM, Xiao L, Zelenka-Wang S, Zhang Y


Proc Natl Acad Sci U S A, 2020

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